Aim: Evaluation of the clinical effect of topical application of doxycycline adjunctive to non-surgical periodontal therapy.Methods: A total of 111 patients suffering from untreated or recurrent moderate to severe periodontitis at 3 different centers (Heidelberg, Frankfurt, Nijmegen) were treated in this double-blind split-mouth study. In each patient, 3 different treatment modalities were assigned randomly to 3 test teeth: scaling and root planing alone (SRP), SRP with subgingival vehicle control (VEH), and SRP with subgingival application of a newly developed biodegradable 15% doxycycline gel (DOXI). At baseline, clinical parameters were measured at all single rooted teeth using a reference splint: PlI, PPD, relative attachment level (RAL-V), GI. 3 strata were generated according to baseline PPD: (i) 5-6 mm, (ii) 7-8 mm, (iii) greater than or equal to9 mm. Not more than 50% active smokers were allowed to each stratum. 3 and 6 months after therapy re-examination was performed by examiners blinded to baseline data and test sites. The statistical comparison of RAL-V gain and PPD reduction between the treatments was based on a repeated measures ANOVA with correction according to Huynh & Feldt. The comparison of SRP versus DOXI was considered as the main study question.Results: 110 patients finished the 3 months and 108 the 6 months examination. The study did not show adverse effects of VEH or DOXI except for one singular inflammation that occurred 2 months after application of the doxycycline gel. DOXI provided statistically significantly more favorable PPD reduction (SRP: -2.4+/-1.4 mm, VEH: -2.7+/-1.6 mm, DOXI: -3.1+/-1.2 mm; SRP versus DOXI VEH versus DOXI p=0.0066) and RAL-V gain (SRP: 1.6+/-1.9 mm, VEH: 1.6+/-2.2 mm, DOXI: 2.0+/-1.7 mm; SRP versus DOXI p=0.027, VEH versus DOXI p=0.038) than SRP and VEH after 6 months.Conclusions: Adjunctive topical subgingival application of a biodegradable 15% doxycycline gel was safe and provided more favorable RAL-V gain and PPD reduction than SRP alone and VEH. Thus, by use of topical doxycycline the threshold for surgical periodontal therapy might be moved toward deeper pockets.